title: Identification of a novel loss-of-function calcium channel gene mutation in short QT syndrome (SQTS6).
abstract: OBJECTIVE
  Short QT syndrome (SQTS) is a genetically determined ion-channel disorder, which may cause malignant tachyarrhythmias and sudden cardiac death. Thus far, mutations in five different genes encoding potassium and calcium channel subunits have been reported. We present, for the first time, a novel loss-of-function mutation coding for an L-type calcium channel subunit.
  
  
  RESULTS
  The electrocardiogram of the affected member of a single family revealed a QT interval of 317 ms (QTc 329 ms) with tall, narrow, and symmetrical T-waves. Invasive electrophysiological testing showed short ventricular refractory periods and increased vulnerability to induce ventricular fibrillation. DNA screening of the patient identified no mutation in previously known SQTS genes; however, a new variant at a heterozygous state was identified in the CACNA2D1 gene (nucleotide c.2264G > C; amino acid p.Ser755Thr), coding for the Ca(v)α(2)δ-1 subunit of the L-type calcium channel. The pathogenic role of the p.Ser755Thr variant of the CACNA2D1 gene was analysed by using co-expression of the two other L-type calcium channel subunits, Ca(v)1.2α1 and Ca(v)β(2b), in HEK-293 cells. Barium currents (I(Ba)) were recorded in these cells under voltage-clamp conditions using the whole-cell configuration. Co-expression of the p.Ser755Thr Ca(v)α(2)δ-1 subunit strongly reduced the I(Ba) by more than 70% when compared with the co-expression of the wild-type (WT) variant. Protein expression of the three subunits was verified by performing western blots of total lysates and cell membrane fractions of HEK-293 cells. The p.Ser755Thr variant of the Ca(v)α(2)δ-1 subunit was expressed at a similar level compared with the WT subunit in both fractions. Since the mutant Ca(v)α(2)δ-1 subunit did not modify the expression of the pore-forming subunit of the L-type calcium channel, Ca(v)1.2α1, it suggests that single channel biophysical properties of the L-type channel are altered by this variant.
  
  
  CONCLUSIONS
  In the present study, we report the first pathogenic mutation in the CACNA2D1 gene in humans, which causes a new variant of SQTS. It remains to be determined whether mutations in this gene lead to other manifestations of the J-wave syndrome.
authors.affiliation: Cardiology, Cardiovascular Center, University Hospital Zurich, Raemistrasse 100, Zurich, Switzerland. christian.templin@usz.ch
authors.forename: Christian
authors.initials: C
authors.lastname: Templin
authors.forename: Jelena-Rima
authors.initials: JR
authors.lastname: Ghadri
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Rougier
authors.forename: Alessandra
authors.initials: A
authors.lastname: Baumer
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kaplan
authors.forename: Maxime
authors.initials: M
authors.lastname: Albesa
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht
authors.forename: Anita
authors.initials: A
authors.lastname: Rauch
authors.forename: Colleen
authors.initials: C
authors.lastname: Puleo
authors.forename: Dan
authors.initials: D
authors.lastname: Hu
authors.forename: Héctor
authors.initials: H
authors.lastname: Barajas-Martinez
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.forename: Hugues
authors.initials: H
authors.lastname: Abriel
authors.forename: Firat
authors.initials: F
authors.lastname: Duru
mesh_terms: D000293:Adolescent; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000503:physiopathology; D015153:Blotting, Western; D015220:Calcium Channels / Q000235:genetics*; D020746:Calcium Channels, L-Type / Q000235:genetics*; D053447:Channelopathies / Q000235:genetics* / Q000503:physiopathology; D004452:Echocardiography; D004562:Electrocardiography; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D014162:Transfection
chemical_list: C425903:CACNA2D1 protein, human; D015220:Calcium Channels; D020746:Calcium Channels, L-Type